Methylamine → HCID 178485532, compound

HRID 1014510Notes

Reaction equation

HRID 1014510 reaction equation
Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:50])[C@@H:34]([CH3:49])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH2:46])[CH:44]=2)[CH2:39][CH2:38]1)=[O:36].[CH3:51][NH2:52].[OH-].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:32][N:33]([CH3:50])[C@H:34]([C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH:46][C:3]3[NH:4][C:5]4=[N:21][CH:20]=[CH:19][C:6]4=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=4[C:15]([NH:52][CH3:51])=[O:17])[N:16]=3)[CH:44]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:49]

Participants

7

Reactant 4

HCID 6329MethylamineHCID 14797Potassium HydroxideHCID 594417711-[(2S)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amineHCID 673162535-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt

Product 1

HCID 178485532HCID 178485532, compoundYield 35%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.043 mmol) and 1-[(2S)-2-(dimethylamino)propanoyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (302 mg, 1.147 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. ESIMS (M+H)+=670. The solids were then added to THF (50 ml)mmol) followed by methylamine 2.0M/THF (16.80 ml, 33.6 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=701. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford the title compound (0.2 g, 35% over three steps). ESIMS (M+H)+=547. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.42 Hz, 3 H) 2.20 (s, 6 H) 2.80 (d, J=4.41 Hz, 3 H) 3.06-3.18 (m, 2 H) 3.55-3.66 (m, 1 H) 3.77 (s, 3 H) 4.11-4.21 (m, 1 H) 4.38-4.48 (m, 1 H) 6.25-6.31 (m, 1 H) 6.83-6.94 (m, 1 H) 6.94-7.02 (m, 2 H) 7.26-7.37 (m, 1 H) 7.57 (s, 1 H) 8.36 (d, J=8.43 Hz, 1 H) 8.54 (s, 1 H) 8.62 (s, 1 H) 10.16 (s, 1 H) 11.26 (s, 1 H).

Workup

  1. washwashed with saturated NaHCO3 (300 ml)
  2. customOrganic layer was removed
  3. concentrationconcentrated by rotary evaporation, solids
  4. customtriturated from ethyl acetate/hexanes
  5. customdried under house vacuum
  6. additionThe solids were then added to THF (50 ml)mmol)
  7. customNext, the crude reaction
  8. custompurified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min)
  9. dissolutionThe isolated pure amide was redissolved in 1,4-dioxane (10 ml)
  10. temperaturethe reaction was heated in the microwave at 120° C. for 20 min
  11. custompurified by silica gel chromatography (DCM to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-b5d3e204a162439c8b6e7edce9203ac5
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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